OVERALL PROJECT SUMMARY (Abbreviated from the original application) The general objective of this proposed renewal for the Columbia University A D R C is to foster innovative research on AD and related disorders (ADRD). Informed by the funding opportunity announcement and influenced by recent advancements, a general theme of this renewal is ?better defining normal aging and the transition from normal aging to the earliest stages of AD?. Since its inception 24 years ago, our ADRC has established an infrastructure for research, fostered interdisciplinary collaborations, established a rich training environment, and promoted outreach and patient recruitment. T he ADRC has a l s o become an active participant in a more global network comprising other institutions, consortia, and community organizations. During its latest cycle, the ADRC has attained most of its goals and its success is evidenced, for example, by the breadth of its scientific achievements and by its #1 ranking in the number of enrolled and active patients. In this proposed renewal, our ADRC will build off of these prior accomplishments and will be motivated by two general goals. The first broad goal is to continue to foster innovative research on ADRD; the second more specific goal is to support the theme of this cycle. These goals will be accomplished with the following specific aims: 1) Supporting and integrating the cores and other resources to facilitate research on ADRD. 2) Fostering our multidisciplinary and multi-department ?local network? at Columbia University with a focus on better understanding the relationship between aging and AD. 3) Fostering our participation in a ?global network? outside of C olumbia University, by playing active roles in national efforts and consortia. 4) Supporting the development of new methodologies, particularly in delineating the transition from aging to AD, and supporting the translation of these findings into better diagnostic, prevention and treatments. 5) Fostering education to patients and in the training of young and new investigators. The cores provide the structural backbone of our ADRC. As evidenced by the success during the previous cycle the same cores and their leaders will be part of this renewal, thereby assuring smooth continuity and the promise of future success. Besides the Administrative Core, these cores include: A Clinical Core led by Dr. Larry Honig; a ?Data Management and Statistical? Core led by Dr. Howard Andrews; a Neuropathology Core led by Dr. Jean-Paul Vonsattel; a Human Genetics Core led by Dr. Christiane Reitz; and, an ?Outreach, Retention, and Education? Core led by Dr. Karen Bell. The specific projects allow the ADRC to mobilize towards its scientific goals, and towards its expansionist goals of fostering new science, investigators, and careers. The ADRC will support three new projects, all led by new investigators. Dr. Adam Brickman will lead Project 1 titled, ?Hippocampal circuitry and white matter abnormalities in aging and AD?. Dr. Sandra Barral will co-lead Project 2 titled, ?Genetic variations linked to the aging hippocampus?. Dr. Ismael Santa-Maria will lead Project 3 titled, ?Post-transcriptional regulation of tau in aging and AD?.